We have obseved that the progeny of cells exposed to cancer initiators contain a subpopulation of cells hypersensitive to subsequent mutational challenge. Increased frequencies of mutation have been observed in these hypermutable cells when treated with cancer promoters that do not display mutational activity in normal cells. This observation documents a mechanism which may be of fundamental significance to multistage carcinogenesis. We propose to test the hypothesis that induction of mutation in hypermutable cells is a property common to a spectrum of cancer promoters, including agents heretofore believed to act through epigenetic mechanisms. Preliminary studies demonstrate that both TPA and cell proliferation are effective in producting mutation in hypermutable cells, but not in control populations. We propose to test three sets of agents for their ability to induce mutation in hypermutable cells. Two sets of agents will be used that are known or believed to alter intracellular free radical prevalence, one by direction action, the other indirectly; the third set are agents known to be animal or human carcinogens, perhaps through promotion, but whose mode of action is unporved or unknown. All agents will be tested at doses which in normal cells are non-toxic, non-mutagenic, and do not inhibit cellular proliferation. Selected antioxidants known to be antitumor agents will also be used to determine if they can inhibit mutation in hypermutable cells.